A Convenient One-Pot Aza-Annulation of Primary Amines, Acryloyl Chloride and Electron-Deficient Allenes

Philip J. Gray; William B. Motherwell; Andrew J. Whitehead

doi:10.1055/s-2007-967955

LETTER

A Convenient One-Pot Aza-Annulation of Primary Amines, Acryloyl Chloride and Electron-Deficient Allenes

Philip J. Gray^a, William B. Motherwell*^a, Andrew J. Whitehead^b
^a Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WC1H OAJ, UK
Fax: +44(20)76797524; e-Mail: w.b.motherwell@ucl.ac.uk;
^b Chemical Development Division, GlaxoSmithKline Research and Development Limited, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

Abstract

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Abstract

The selection of electron-deficient allenes as substrates for highly regioselective vinylogous amide formation leads to a convenient one-pot [3+3] annulation sequence for the construction of highly functionalized cyclic enamides. By the selection of the appropriate amines, tandem bicyclisations were achieved, thereby allowing facile access to azabicyclo[4.3.0] systems known to be useful precursors to the biologically important indolozine alkaloids.

Key words

allenes - enaminones - Michael additions - regioselectivity - heterocycles

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References

References and Notes

<A NAME="RD36506ST-1A">1a</A> Baliah V. Jeyaraman R. Chandrasekaran L. Chem. Rev. 1983, 83: 379

<A NAME="RD36506ST-1B">1b</A> Fodor GB. Colosanti B. In Alkaloids: Chemical and Biological Perspectives Vol. 3: Pelletier SW. Wiley; New York: 1985. p.1-90

<A NAME="RD36506ST-1C">1c</A> Felpin FX. Lebreton J. Tetrahedron 2004, 60: 10127

<A NAME="RD36506ST-2">2</A> Takasu K. Nishida N. Tomimura A. Ihara M. J. Org. Chem. 2005, 70: 3957

<A NAME="RD36506ST-3A">3a</A> Lee E. Li KS. Lim J. Tetrahedron Lett. 1996, 37: 1445

<A NAME="RD36506ST-3B">3b</A> Hanessian S. Reinhold U. Ninkovic S. Tetrahedron Lett. 1996, 37: 8967

<A NAME="RD36506ST-4">4</A> Marson CM. Grabowska U. Walsgrove T. J. Org. Chem. 1992, 57: 5045

<A NAME="RD36506ST-5">5</A> Stockman RA. Szeto P. Thompson SHJ. Hadley MS. Lathbury DC. Gallagher T. Synlett 1996, 853

<A NAME="RD36506ST-6">6</A> Hickmott PW. Sheppard G. J. Chem. Soc. C 1971, 2112

<A NAME="RD36506ST-7A">7a</A> Paulvannan K. Stille JR. J. Org. Chem. 1992, 57: 5319

<A NAME="RD36506ST-7B">7b</A> Paulvannan K. Stille JR. J. Org. Chem. 1994, 59: 1613

<A NAME="RD36506ST-7C">7c</A> Cook GR. Beholz LG. Stille JR. J. Org. Chem. 1994, 59: 3575

<A NAME="RD36506ST-7D">7d</A> Beholz LG. Benovsky P. Ward DL. Barta NS. Stille JR. J. Org. Chem. 1997, 62: 1033

<A NAME="RD36506ST-8A">8a</A> Danishefsky SJ. Bornmann WG. Coburn CA. Shen W. J. Org. Chem. 1993, 58: 611

<A NAME="RD36506ST-8B">8b</A> Fang FG. Danishefsky SJ. Tetrahedron Lett. 1980, 21: 2783

<A NAME="RD36506ST-9">9</A> Agami C. Hamon L. Kadouri-Puchot C. Le Guen VJ. J. Org. Chem. 1996, 61: 5736

<A NAME="RD36506ST-10">10</A> Murphy JP. Hadden M. Stevenson PJ. Tetrahedron 1997, 53: 11827

<A NAME="RD36506ST-11">11</A> Ma S. Yu S. Yin S. J. Org. Chem. 2003, 68: 8996

<A NAME="RD36506ST-12">12</A> For the use of acetylenes in aza-annulation reactions, see: Beholz LG. Benovsky P. Ward DL. Barta NS. Stille JR. J. Org. Chem. 1997, 62: 1033

Prepared as outlined in ref. 11.

<A NAME="RD36506ST-14">14</A> Bayer A. Maier ME. Tetrahedron 2004, 6665

<A NAME="RD36506ST-15A">15a</A> Cardellini L. Carloni P. Greci L. Tosi G. Andruzzi R. Marrosu G. Trazza A. J. Chem. Soc., Perkin Trans. 2 1990, 2117

<A NAME="RD36506ST-15B">15b</A> Kreher T. Sonnenschein H. Schmidt L. Huing S. Liebigs Ann. Chem. 1994, 1173

<A NAME="RD36506ST-15C">15c</A> Okazaki S. Kurosaki A. Bull. Chem. Soc. Jpn. 1987, 2833

<A NAME="RD36506ST-15D">15d</A> Michael JP. Nat. Prod. Rep. 1991, 8: 51

<A NAME="RD36506ST-16">16</A> Tidwell TT. Far AR. J. Comb. Chem. 1999, 458

<A NAME="RD36506ST-17">17</A> Allenic ester 14b is commercially available; all others were prepared according to the procedure of Lang and Hansen, see: Lang RW. Hansen H.-J. Helv. Chim. Acta 1980, 63: 438

General Procedure for the Synthesis of Enamides 10a-e and Spectroscopic Data for 10c.
Amine 9c (1.0 mmol) was added to a solution of the allenic ketone (1.0 mmol) in anhyd MeCN (10 mL) at r.t. and then heated to reflux for 40 min under an atmosphere of nitrogen. The reaction mixture was cooled to r.t. and acryloyl chloride (1.1 mmol) was added. The reaction mixture was heated to reflux for a subsequent 1.5 h, cooled and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (4:1 PE-EtOAc) to give the product (10c) as a clear oil.
¹H NMR (300 MHz, CDCl₃): δ = 1.65 (m, 1 H, CH), 2.01 (s, 3 H, Me), 2.14 (m, 1 H, CH), 2.44 (m, 1 H, CH), 2.56 (m, 1 H, CH), 2.90 (d, 1 H, J = 13.8 Hz, CH₂Ph), 3.23 (d, 1 H, J = 13.8 Hz, CH₂Ph), 3.77 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 4.62 (d, 1 H, J = 2.4 Hz, =CH), 4.82 (d, 1 H, J = 2.4 Hz, =CH), 4.96 (s, 2 H, CH₂N), 6.70-6.87 (m, 3 H, ArH), 7.00 (m, 2 H, ArH), 7.19-7.46 (m, 3 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 206.7, 169.3, 149.2, 148.2, 146.7, 135.7, 130.2, 129.5, 128.3, 127.1, 119.5, 111.0, 110.5, 96.9, 56.1, 55.9, 47.4, 41.7, 29.0, 25.7, 25.2, 21.0. HRMS-FAB: m/z calcd for C₂₄H₂₇N0₄: 394.20182; found [MH]⁺: 394.20222. IR (neat): ν_max = 3012, 2935, 2835 (CH), 1708, 1670 (C=O) cm^-1.

Procedure for the Synthesis of 13. Procedure identical to that for ref. 10c, however, 40 mg of p-TsOH was added after the addition of acryloyl chloride. The pyrrole was obtained as a white solid, mp 72-74 °C.
¹H NMR (300 MHz, CDCl₃): δ = 1.79 (m, 1 H, CH), 2.19 (s, 3 H, Me), 2.36 (m, 1 H, CH), 2.57-2.69 (m, 2 H, CH₂CO), 3.14 (d, 1 H, J = 13.8 Hz, CH₂Ph), 3.41 (d, 1 H, J = 13.8 Hz, CH₂Ph), 6.34 (t, 1 H, J = 3.3 Hz, ArH), 6.39 (m, 1 H, ArH), 7.05 (m, 2 H, ArH), 7.23-7.28 (m, 3 H, ArH), 7.41 (m, 1 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 207.3, 167.7, 135.3, 134.0, 130.0, 128.4, 127.2, 117.6, 112.8, 111.9, 52.9, 43.3, 30.4, 28.2, 26.7. HRMS-FAB: m/z calcd for C₁₇H₁₇NO₂: 268.13375; found [MH]⁺: 268.13321. IR (nujol): ν_max = 2923, 2852, (CH), 1705 (C=O), 1456, 1400 cm^-1.

General Procedure for the Synthesis of Azabicyclo[4.3.0] Systems 15a-c and 17.
A solution of the allene (1.1 mmol), amine (1.1 mmol) and p-TsOH (40 mg) was heated to reflux for 40 min, cooled to r.t. and treated with acryloyl chloride (1.1 equiv). The reaction mixture was heated for a subsequent 8 h, cooled and concentrated at reduced pressure. Purification by chromatography (PE-EtOAc, 3:1) gave 15c as a pale yellow solid, mp 55-57 °C.
¹H NMR (300 MHz CDCl₃): δ = 1.70 (t, 3 H, J = 7.1 Hz, CH₃,), 2.25 (m, 1 H, CH₂CO) 2.40 (m, 1 H, CH₂CHCO₂Et), 2.70 (m, 1 H, CH₂CHCO₂Et), 2.99 (m, 1 H, CH₂CO), 3.80 (s, 2 H, CH₂Ph), 3.94 (m, 1 H, CHCO₂Et) 4.03 (m, 2 H, CH₂CH₃) 6.10 (d, 1 H, J = 3.4 Hz, ArH), 7.14-7.37 (m, 5 H, ArH), 7.37 (d, 1 H, J = 3.4 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 171,6, 167.5, 140.2, 128.5, 128.4, 126.1, 125.1, 124.2, 116.8, 114.6, 61.4, 36.8, 32.0, 30.0, 24.8, 14.0. HRMS-FAB: m/z calcd for C₁₈H₁₉NO₃: 298.14431; found [MH]⁺: 298.14378. IR (nujol): ν_max = 2854 (CH), 1728 (CO), 1458, 1373, 1319, 1172 cm^-1.